Background

Bisphosphonates inhibit osteoclast-mediated bone resorption. In patients
with breast cancer metastatic to bone they have been shown to reduce the
incidence of hypercalcemia, bone pain and fractures. One bisphosphonate,
clodronate, also reduced the number of new skeletal metastases in patients
with advanced breast cancer but no preexisting bone metastases.

This study was designed to investigate the effect of clodronate on bony
and visceral metastases in patients with primary breast cancer who had
no evidence of visceral or bone metastases but who did have tumor cells
in a bone marrow biopsy specimen obtained at the time of enrollment.

Methods

Patients

Inclusion criteria:

Primary breast cancer of any size (T0-T4), with or without ipsilateral
lymph nodes (N0-N2).

All patients underwent either mastectomy or breast-conserving surgery
with radiation, as well as axillary lymphadenectomy and bone-marrow biopsy.

Patients were then randomized to receive or not to receive treatment
with clodronate, 1600 mg daily for two years (this was not a placebo controlled
study).

After randomization, and based on prognostic factors (lymph node status,
menopausal status, estrogen receptor status and tumor size), the decision
was made whether or not to administer adjuvant therapy and what specific
therapy to administer. Decisions about adjuvant therapy were not modified
by the results of the bone marrow biopsy.

All patients who subsequently developed bone metastases were treated
with clodronate. Patients with disease progression / metastases were treated
with anti-neoplastic agents and/or hormonal therapy.

Follow-up

Patients were seen every 3-4 months for history, physical examination
and bloodwork and yearly for bone scanning, chest x-ray, liver ultrasonography
and mammograms.

The primary study endpoints were the incidence and number new bony and
visceral metastases and the time to their appearance.

Results

Patients

302 patients were randomized, 157 to the clodronate group, 145 to the
control group. Patients excluded from evaluation (non-compliance, drug
side effects, loss of follow up) were 3 in the control group and 15 in
the clodronate group.

Prognostic factors were well matched between the groups.

The median age of patients was 51 years. In the control group 39% were
pre-menopausal vs. 36% in the clodronate group.

Histologic grade was I or II in 73% of the control group vs. 68% of
the clodronate group.

Tumors were stage T1 or T2 in 83% of patients, lymph node status was
negative in 47%, estrogen receptor status was positive in 73%, progesterone
status was positive in 63%.

19% of patients received no adjuvant chemotherapy. The remaining 81%
received one of five regimens, mainly tamoxifen and/or cytoxan-methotrexate-fluorouracil,
well balanced between the two groups.

Metastases

Median follow-up was 36 months.

Bone metastases: 12 (8%) in the clodronate group, vs. 25 (17%)
in the control group (p=0.003). Mean number of bony metastases per patient:
3.1 vs 6.3 (p=0.004).

There were 6 deaths in the clodronate group (4%) vs 22 in the control
group (15%) (p=0.001).
Kaplan-Meier

These results were confirmed in Kaplan-Meier curves of survival without
metastases and overall survival.

Author's discussion

The authors make a number of points in their discussion:

These women all had a high risk of distant metastasis, based on the presence
of tumor cells in the bone marrow. They state that tumor cells were found
in the marrow in 55% of node-positive patients and in 31% of node negative
patients.

The beneficial effect of bisphosphonates on bony metastases has been suggested
by animal experiments and by trials in women with documented bone metastases.
In the early phase of metastasis to bone, tumor cells activate osteoclasts.
There is evidence that growth factors which may promote the growth of tumor
cells are released when bone is degraded. Bisphosphonates inhibit the activity
of osteoclasts, which may account for some of the favorable effects seen
here. Other possible mechanisms include the induction of apoptosis
and alteration of adhesion molecules on tumor and bone cells.

Because of the limited follow-up period, it is unclear whether the reduction
in bone metastases seen was due to a delay in their appearance or an actual
prevention of their development.

Unlike the effect on bone metastasis, the effect on visceral metastasis
was unexpected. Possible explanations include the same mechanisms that
are thought to apply to bone metastasis (apoptosis and alteration of adhesion
molecules), as well as some sort of synergy with cytotoxic agents.

Comment

In this study, clodronate was administered orally for two years to patients
with breast cancer, without evidence of metastatic disease but with tumor
cells found on bone marrow biopsy. During a mean follow-up of 36 months,
there was a significant decrease in the incidence of new bony metastases
and an increase in the time to appearance of this complication. Surprisingly,
a similar effect was noted on visceral metastases and on overall survival.

Complications from breast cancer can occur many years later. Thus, as
the authors point out, it is impossible to tell whether their results indicate
definitive prevention of metastasis and death for some women, or a delay
in the occurrence of these events. Looking at the shape of the Kaplan-Meier
curves in the article, one has the impression that the divergence is due
to a delay in the occurrence of events. However, even if cure is preferable
to delay, a significant delay is much better than no delay.

It is surprising that this trial was randomized but not blinded or placebo-controlled.
It is not stated that the radiologists who interpreted the bone scans were
blinded to the treatment assignment. This in troduces some concern about
observer bias in interepretation of results and symptoms, when patients
came for follow-up.

There is another aspect of the study design that I find troubling. In
order to participate, women had to undergo an iliac-crest bone-marrow aspirate.
It is specifically stated that adjuvant chemotherapy decisions did not
take into account the results of the bone-marrow biopsy. Thus, it would
seem that those women who were randomized to the control group received
no benefit from this procedure and the information it provided. This
is particularly troubling since the presence of tumor cells in the bone
marrow indicates a worse prognosis and thus might justify a more aggressive
adjuvant therapy approach. Despite the presence of tumor cells in the marrow,
19% of the women received no adjuvant therapy at all, including tamoxifen.
Would more aggressive adjuvant therapy in all patients have diminished
the magnitude of clodronate's effect seen in this study? Unfortunately,
the authors do not give any data on the effect of clodronate therapy in
the various subgroups of adjuvant therapy.

Finally, since all patients in this study had documented tumor cells
in the bone marrow, it is not clear how the results would apply to large
proportion of women (up to 70% of those with negative axillary nodes) who
do not have tumor cells in their marrow.

These objections aside, the role of bisphosphonates in the treatment
of breast cancer is likely to increase, with many questions that remain
to be answered concerning the effectiveness of various agents, their combination
with other therapies and the appropriate target populations.